Protein formulations containing amino acids
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Publication Number
US-9364542-B2
Publication Date
2016-06-14
Expiration Date
Abstract
Provided are stable protein formulations that contain at least one amino acid. In certain embodiments, amino acid combinations either at least two, or three, or four, or more amino acids are included. By virtue of inclusion of the amino acids, the formulation has low viscosity and a protein in the formulations is physically, chemically, and biological stable even at high concentrations. In further embodiments, by virtue of inclusion of the amino acids, a protein in the formulations is physically, chemically, and biological stable even at high concentrations.
Core Innovation
The invention relates to a stable liquid pharmaceutical formulation comprising an antibody selected from adalimumab, alemtuzumab, alirocumab, basiliximab, bevacizumab, daratumumab, infliximab, panitumumab, ranibizumab, rituximab, or trastuzumab, and one or more amino acids. The formulation stabilizes the antibody in the formulation and addresses physical, chemical, and biological stability, including reduced aggregation, precipitation, and gelation.
The stability-providing amino acids include serine, threonine, alanine, glycine, and valine, and one or more further amino acids selected from isoleucine, asparagine, glutamine, and aspartic acid. In addition, viscosity reduction is achieved by including proline, and the viscosity of the formulation is less than 100 cP.
The disclosure describes formulations at high protein concentration and evaluates stability and injectability-related properties, including turbidity and viscosity-related measurements, with analytical methods such as SEC-HPLC and other assessments. Example antibodies include infliximab, trastuzumab, and rituximab, where amino acid combinations improve stability while lowering viscosity.
Claims Coverage
The independent claim defines a stable liquid pharmaceutical formulation with an antibody and two functional amino-acid roles: stabilization and viscosity reduction. It includes three inventive features and requires that the resulting viscosity is less than 100 cP.
Stable liquid formulation with specified antibody
A stable liquid pharmaceutical formulation comprising an antibody selected from adalimumab, alemtuzumab, alirocumab, basiliximab, bevacizumab, daratumumab, infliximab, panitumumab, ranibizumab, rituximab, or trastuzumab.
Amino-acid stabilization of the antibody
One or more amino acids to stabilize the antibody, the stabilizing amino acids including serine, threonine, alanine, glycine, and valine and one or more further amino acids selected from isoleucine, asparagine, glutamine, and aspartic acid.
Proline-based viscosity reduction
One or more amino acids to reduce the viscosity of the formulation, the viscosity-reducing amino acids including proline, wherein the viscosity of the formulation is less than 100 cP.
The claim coverage centers on a stable liquid formulation where selected amino acids stabilize a specified antibody and proline-containing amino acids reduce viscosity, with a viscosity limit of less than 100 cP.
Stated Advantages
Improved physical, chemical, and biological stability, including reduced aggregation, precipitation, and gelation.
Lowered viscosity of the formulation to enable injection, with viscosity less than 100 cP.
Improved injectability and reduced aggregation/precipitation.
Documented Applications
Stable liquid pharmaceutical formulations for antibodies including infliximab, trastuzumab, rituximab, cetuximab, bevacizumab, ranibizumab, and palivizumab.
Formulation stabilization and injectability/viscosity improvement for monoclonal antibody products, including effects under high-temperature and particle formation conditions.
Viscosity and aggregate-profile testing for liquid antibody formulations using stability and viscosity-related assays.
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